This invention relates to novel compounds of general formula I or pharmaceutically acceptable salts thereof, which lower plasma glucose levels and/or insulin levels in vivo and/or inhibit the production of PEPCK enzyme and/or lower glucose and/or insulin levels in cultured cells and are therefore useful in the treatment of non-insulin dependent diabetes mellitus (NIDDM). Diabetes mellitus is a syndrome characterized by abnormal insulin production, increased urinary output and elevated blood glucose levels. There are two major subclasses of diabetes mellitus. One is the insulin-dependent diabetes mellitus (IDDM or Type 1), formerly referred to as juvenile onset diabetes since it was evident early in life, and non-insulin dependent diabetes mellitus (NIDDM or Type 2), often referred to as maturity-onset diabetes. Exogenous insulin by injection is used clinically to control diabetes but suffers from several drawbacks. Insulin is a protein and thus cannot be taken orally due to digestion and degradation but must be injected. It is not always possible to attain good control of blood sugar levels by insulin administration. Insulin resistance sometimes occurs requiring much higher doses of insulin than normal. Another shortcoming of insulin is that while it may control hormonal abnormalities, it does not always prevent the occurrence of complications such as neuropathy, retinopathy, glomerulosclerosis, or cardiovascular disorders. Insulin regulates glucose homeostasis mainly by acting on two targets tissues: liver and muscle. Liver is the only site of glucose production and skeletal muscle the main site of insulin mediated glucose uptake.
Orally effective antihyperglycemic agents are used to reduce blood glucose levels and to reduce damage to the nervous, retinal, renal or vascular systems through mechanisms affecting glucose metabolism. Such agents act in a variety of different mechanisms including inhibition of fatty acid oxidation, a-glycosidase inhibition, antagonism of a2-receptors and inhibition of gluconeogenesis. Two classes of compounds have predominated: the biguanides as represented by phenformin and the sulfonylureas as represented by tolbutamide (Orinase®). A third class of compounds which has shown antihyperglycemic activity are the thiazolidinediones. Recently a member (troglidazone) of this family was introduced for the treatment of Type 2 diabetes.
PEPCK is present at relatively high specific activity in liver, renal cortex, and white fat (R. M. O'Brien, Diabetes Care, 1990, 13, 327-339). It catalyzes the conversion of oxaloacetate to phosphonoenolpyruvate, the rate-limiting step in hepatic and renal gluconeogenesis, and it is essential for the synthesis of a-glycerophosphate in adipose tissue. Given that PEPCK catalyzes the rate-limiting step in gluconeogenesis, it is reasonable to conclude that the activity of the PEPCK gene determines the rate of this important metabolic process (E. Sharfir, Frontiers In Diabetes Research, 1998, John Libbey & Company, Ltd, pp 304-315). PEPCK activity is altered in vivo by glucagon, glucocorticoids, insulin, epinephrine, thyroxine and glucose. The primary effectors are glucagon and glucocorticoids, which increase the synthesis of PEPCK, and insulin, which decreases its synthesis. All of these effects appear to result from alterations in the amount of PEPCK mRNA, which in turn result from changes in the rate of transcription of the PEPCK gene. Gluconeogenesis rates are increased two- to three-fold in patients with NIDDM, and gluconeogenesis is the predominant mechanism responsible for fasting hyperglycemia in NIDDM (A. Consoli, et.al. Diabetes, 1989, 38, 550-557). Modulation of the transcription of the PEPCK gene may lead to glucose lowering in NIDDM patients.
Clinical Correlation: Compounds that inhibit or modulate glucose production in cultured hepatocytes from gluconeogenic precursors should inhibit gluconeogenesis in man and cause a reduction in the circulating plasma glucose level. Known gluconeogenic inhibitors that cause decreases in blood glucose in vivo have been shown to be active in this assay. (References: Berry M N, Edwards A M, Barritt G J. Isolated hepatocytes, preparation properties and applications in laboratory techniques in Biochemistry and Molecular Biology. 1983; 65:55-63; Exton, J. H. The perfused rat liver in Methods in Enzymology XXXIX, part D (Hormone Action), pp 25-36 (1975). Eds.; J. G. Hardman and B. W. O'Malley. Goodman M N. Effect of 3-mercaptopicolinic acid on gluconeogenesis and gluconeogenic metabolite concentrations in the isolated perfused rat liver. Biochem. J. 1975; 150:137-139; Jomain-Baum M, Schramm V L, Hanson R W. Mechanism of 3-mercaptopicolinic acid inhibition of hepatic phosphoenol pyruvate carboxykinase (GTP). J. Biol. Chem. 1976; 251:37-44; Lowry O H, Rosebrough N J, Farr A L, Randall R J: Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951; 193:265-275; Musmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth. 1983; 65: 55-63).